Trigonelline attenuates valproic acid-induced autism-like behaviours in rats: histopathological changes of the hippocampus, modulation of gene expressions related to neuroinflammation and blood-brain barrier permeability.

Protective Effects of Prenatal Bacopa monnieri Extract Against Valproic Acid-Induced Autism-like Behavioral and Neurohistological Alterations in Mice

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by impaired social communication and repetitive behaviors. Oxidative stress is increasingly recognized as a key contributor to the neuro-degeneration and behavioral abnormalities associated with ASD. Bacopa monnieri (BM), a medicinal herb with potent antioxidant and neuro-protective properties, has shown promise in mitigating oxidative damage. This study evaluated the preventive effects of BM extract on behavioral and neuro-histological alterations in a valproic acid (VPA)-induced mouse model of ASD. Pregnant mice received BM extract (400 mg/kg, orally) throughout gestation, while VPA (600 mg/kg) was administered intraperitoneally on embryonic day 12 (E12). Behavioral assessments included the open field test, righting reflex, three-chamber social interaction, marble burying, and hot plate tests. Oxidative stress markers, malondialdehyde (MDA) and glutathione (GSH), were quantified in hippocampal and cerebellar tissues. BM-treated offspring showed significant behavioral improvements, including reduced hyperactivity in the open field test (p < 0.0001), along with restored brain tissue architecture. Moreover, BM extract decreased MDA levels and elevated GSH concentrations, indicating attenuation of oxidative stress. In conclusion, Bacopa monnieri extract exerts protective effects against autism-like symptoms by enhancing antioxidant defenses and preserving neural integrity, suggesting its potential as a natural preventive strategy for ASD.

Salidroside enhances hippocampal neurogenesis in a valproic acid-induced mouse model of autism by suppressing neuroinflammation.

OBJECTIVE Neuroinflammation plays a pivotal role in the pathogenesis of autism spectrum disorder (ASD) and represents a potential therapeutic target. Salidroside (SLDS), a bioactive compound isolated from Rhodiola rosea L., exhibits potent anti-inflammatory and neuroprotective effects in various neurological disorders; however, its therapeutic efficacy in ASD remains to be fully established. This study investigated whether SLDS ameliorates autism-like behaviors and hippocampal neuroinflammation in a valproic acid (VPA)-induced mouse model. METHODS A total of 92 male C57BL/6 J mice were randomly assigned to four groups (n = 23 per group). Mice received a subcutaneous injection of VPA or saline on postnatal day 14 (P14), followed by intraperitoneal administration of SLDS or saline from postnatal day 28 (P28) for seven consecutive days. Behavioral assessments were conducted at 8 weeks of age. Hippocampal neuroinflammation, microglial polarization, and neurogenesis were analyzed by molecular, immunofluorescence, and histological techniques. RESULTS VPA-exposed mice exhibited social interaction deficits, increased repetitive behaviors, elevated levels of pro-inflammatory cytokines, upregulated expression of inflammation-related proteins, microglial activation, and impaired hippocampal neurogenesis. SLDS treatment significantly attenuated these VPA-induced abnormalities. CONCLUSION Collectively, these findings suggest that SLDS represents a promising therapeutic candidate for ASD by mitigating neuroinflammation and restoring hippocampal function. Nevertheless, given that these observations are derived from preclinical models, further validation in translationally relevant experimental systems and clinical investigations is warranted before extrapolation to human therapeutic applications.

Formononetin Attenuates Seizure Severity and Cognitive Deficits in PTZ-Kindled Rats with Associated Changes in Oxidative Stress and P2 X 7/IL-1β/Glutamate Signalling Markers

Neuroinflammatory Response to Postnatal Administration of Valproic Acid in Wistar Rats as a Mechanism for the Development of Autism Spectrum Disorders: The Role of Neutrophils

Highlights What are the main findings? Postnatal administration of VPA induces an autism-like phenotype in rats. Autism-like behavior is associated with increased activity of neutrophil elastase, α1-proteinase inhibitor, and the complement system, indicating systemic inflammation. What are the implications of the main findings? Increased activity of neutrophil elastase in the cerebellum indirectly indicates neutrophil infiltration into the central nervous system. Neutrophils are suggested to be involved in the neuroinflammatory mechanism of autism spectrum disorders. Abstract Background/Objectives: According to current concepts, neuroinflammation is one of the putative causes of autism spectrum disorders (ASD) development. However, the role of neutrophils in neuroinflammation remains insufficiently studied. The study was aimed to determine the role of neutrophils in the neuroinflammatory mechanism of ASD development based on a comparative analysis of physiological and behavioral disturbances and the inflammatory response to early postnatal administration of valproic acid (VPA) to Wistar rats. Methods: The study was performed on 38 rat pups of both sexes, half of which were injected intraperitoneally with an aqueous solution of VPA at a dose of 150 mg/kg from 6 to 12 postnatal days (PND); control rats received water. Standard physiological and behavioral tests were used: weight monitoring, pain sensitivity (Hot Plate test) on 25 PND, and social behavior (sib/non-sib test) on 55 PND. Neutrophil elastase (NE) and alpha1-proteinase inhibitor (α1-PI) activity in serum and cerebellum homogenate was measured spectrophotometrically. Complement system (CS) activity was analyzed by the death rate of Tetrahymena pyriformis ciliates in the presence of rat serum. Results: Early postnatal administration of VPA to Wistar rats induces physiological and behavioral changes characteristic of ASD, confirming the validity of the experimental model used. These changes are accompanied by increased activity of inflammatory factors (CS, α1-PI, NE) in the rat serum, indicating the development of inflammation. VPA treatment increased NE activity in the cerebellum, which may indicate neutrophil infiltration of the brain and neuroinflammation development. Conclusions: The data obtained indicate the role of neutrophils in neuroinflammatory mechanisms of ASD development.

Forsythoside E alleviates chronic unpredictable mild stress-induced depressive-like behaviors in mice: associations with blood-brain barrier integrity and neuroinflammatory changes in the prefrontal cortex.

RATIONALE Persistent stress-related depression has increasingly been associated with neuroinflammatory activation and impairment of blood-brain barrier (BBB) function. Forsythoside E (FE), a phenylethanoid glycoside isolated from Forsythia suspensa, is known to exert anti-inflammatory and cytoprotective effects. OBJECTIVES Given that its specific role in stress-related depressive states and associated BBB abnormalities remains insufficiently defined, this study aimed to evaluate whether FE could mitigate behavioral impairment and modulate the neurovascular inflammatory microenvironment in a chronic stress model. METHODS Male C57BL/6 mice were subjected to chronic unpredictable mild stress (CUMS) for 6 weeks, with FE (50 mg/kg/day) administered orally starting from day 21. Behavioral alterations were evaluated using the sucrose preference, novelty-suppressed feeding, tail suspension, forced swimming, and open-field paradigms. ELISA, immunofluorescence, and Evans blue extravasation were employed to quantify inflammatory changes, BBB leakage, and perivascular IL-17A and VEGFA expression in the prefrontal cortex (PFC). RESULTS FE markedly attenuated CUMS-induced behavioral abnormalities, including reduced sucrose preference, prolonged feeding latency, increased immobility, and diminished central exploration, though body weight loss was not significantly corrected. FE treatment was associated with reduced TNF-α, IL-6, IL-1β, and IL-17A levels in the PFC, reduced microglial accumulation, decreased Evans blue extravasation, and reduced perivascular IL-17A and VEGFA expression. CONCLUSIONS FE was associated with alleviation of depressive-like behaviors in CUMS-exposed mice. These effects are accompanied by reduced neuroinflammatory responses, decreased BBB permeability, and alterations in IL-17A and VEGFA expression in the prefrontal cortex. These findings suggest a potential involvement of neurovascular and inflammatory processes in the observed effects of FE, although causal mechanisms require further investigation.

NDP-MSH rescues LPS-induced neuroinflammation, synaptic deficits, and depressive-like behaviors in mice: involvement of MC1R–cAMP/PKA signaling

Introduction Inflammatory processes contribute significantly to the pathophysiology of depression. Although the melanocortin system is well known to regulate inflammation, the specific contribution of melanocortin 1 receptor (MC1R) and its endogenous ligand, α-melanocyte-stimulating hormone (α-MSH), to inflammation-associated depression remains unclear. Methods Systemic lipopolysaccharide (LPS) administration was used to establish an inflammation-associated depression model in mice. Depressive-like behaviors, synaptic functions, and metabolic alterations were evaluated using behavioral tests, patch-clamp recordings, and untargeted metabolomic profiling. To examine the functional involvement of MC1R, adeno-associated virus (AAV)-mediated selective Mc1r overexpression was performed in the medial prefrontal cortex (mPFC). Results LPS administration induced depressive-like behaviors in mice, accompanied by microglial activation and a significant reduction in MC1R expression in the prefrontal cortex (PFC). Treatment with MC1R endogenous ligand α-MSH mimetic Nle4-DPhe7-α-MSH (NDP-MSH) markedly attenuated LPS-induced depressive-like behaviors, enhanced MC1R, postsynaptic density protein 95 (PSD95), glutamate receptor 1 (GluA1) and protein kinase A (PKA) phosphorylation. PKA inhibitor H89-mediated inhibition of the cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) pathway partially but robustly abolishes the behavioral, anti-inflammatory, and synaptic protective effects of NDP-MSH. Additionally, untargeted metabolomics confirmed that NDP-MSH effectively corrected LPS-induced metabolic dysregulation, a therapeutic effect that was robustly suppressed by H89; this metabolic remodeling was closely associated with purine metabolism, pantothenate, and coenzyme A biosynthesis. Critically, AAV-mediated Mc1r overexpression in the mPFC was sufficient to rescue LPS-induced depressive-like phenotypes. Conclusion This study highlights MC1R-related signaling in the PFC as an important contributor to inflammation-associated depression and suggests that NDP-MSH alleviates inflammation-associated depressive-like behaviors in association with melanocortin signaling involving MC1R and downstream cAMP/PKA activation.